Uracil within DNA: an actor of antiviral immunity

Uracil is a natural base of RNA but may appear in DNA through two different pathways including cytosine deamination or misincorporation of deoxyuridine 5'-triphosphate nucleotide (dUTP) during DNA replication and constitutes one of the most frequent DNA lesions. In cellular organisms, such lesions are faithfully cleared out through several universal DNA repair mechanisms, thus preventing genome injury. However, several recent studies have brought some pieces of evidence that introduction of uracil bases in viral genomic DNA intermediates during genome replication might be a way of innate immune defence against some viruses. As part of countermeasures, numerous viruses have developed powerful strategies to prevent emergence of uracilated viral genomes and/or to eliminate uracils already incorporated into DNA. This review will present the current knowledge about the cellular and viral countermeasures against uracils in DNA and the implications of these uracils as weapons against viruses

Thyroid hormones down-regulate thyrotropin beta mRNA level in vivo in the turbot (Psetta maxima)

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Biosynthesis pathways of ribonucleotides and deoxyribonucleotides in mammalian cells and the possible consequence of the misincorporation and repair of uracil residues in DNA

synthesis of AMP, CMP, GMP and UMP ribonucleotides allows the formation of dATP, dCTP, dGTP, dTTP and dUTP deoxyribonucleotides, which can be readily incorporated in DNA by cellular DNA polymerases. Note that dTTP derives from dUTP hydrolysis. Abbreviations: A, adenine; C, cytosine; G, guanine; T, thymine; U, uracil; MP, monophosphate; DP, diphosphate; TP, triphosphate; rNDP, ribonucleotide diphosphate; NMPK, nucleotide monophosphate kinase; NDPK, nucleotide diphosphate kinase.<p><b>Copyright information:</b></p><p>Taken from "Uracil within DNA: an actor of antiviral immunity"</p><p>http://www.retrovirology.com/content/5/1/45</p><p>Retrovirology 2008;5():45-45.</p><p>Published online 5 Jun 2008</p><p>PMCID:PMC2427051.</p><p></p

Mutations on VEEV nsP1 relate RNA capping efficiency to ribavirin susceptibility

International audienceAlphaviruses are arthropod-borne viruses of public health concern. To date no efficient vaccine nor antivirals are available for safe human use. During viral replication the nonstructural protein 1 (nsP1) catalyzes capping of genomic and subgenomic RNAs. The capping reaction is unique to the Alphavirus genus. The whole three-step process follows a particular order: (i) transfer of a methyl group from S-adenosyl methionine (SAM) onto a GTP forming m7GTP; (ii) guanylylation of the enzyme to form a m7GMP-nsP1adduct; (iii) transfer of m7GMP onto 5′-diphosphate RNA to yield capped RNA. Specificities of these reactions designate nsP1 as a promising target for antiviral drug development. In the current study we performed a mutational analysis on two nsP1 positions associated with Sindbis virus (SINV) ribavirin resistance in the Venezuelan equine encephalitis virus (VEEV) context through reverse genetics correlated to enzyme assays using purified recombinant VEEV nsP1 proteins. The results demonstrate that the targeted positions are strongly associated to the regulation of the capping reaction by increasing the affinity between GTP and nsP1. Data also show that in VEEV the S21A substitution, naturally occurring in Chikungunya virus (CHIKV), is a hallmark of ribavirin susceptibility. These findings uncover the specific mechanistic contributions of these residues to nsp1-mediated methyl-transfer and guanylylation reactions

APOBEC3 family members and their associated roles in exogenous viruses and endogenous retroelements restriction

Data are compiled from [27, 77, 87, 90, 126-140].<p><b>Copyright information:</b></p><p>Taken from "Uracil within DNA: an actor of antiviral immunity"</p><p>http://www.retrovirology.com/content/5/1/45</p><p>Retrovirology 2008;5():45-45.</p><p>Published online 5 Jun 2008</p><p>PMCID:PMC2427051.</p><p></p

Phylogenetically based establishment of a dengue virus panel, representing all available genotypes, as a tool in dengue drug discovery

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Optimization of a fragment linking hit toward Dengue and Zika virus NS5 methyltransferases inhibitors

International audienceNo antiviral drugs to treat or prevent life-threatening flavivirus infections such as those caused by mosquito-borne Dengue (DENV) and more recently Zika (ZIKV) viruses are yet available. We aim to develop, through a structure-based drug design approach, novel inhibitors targeting the NS5 AdoMet-dependent mRNA methyltransferase (MTase), a viral protein involved in the RNA capping process essential for flaviviruses replication. Herein, we describe the optimization of a hit (5) identified using fragment-based and structure-guided linking techniques, which binds to a proximal site of the AdoMet binding pocket. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 30 and 33 (DENV IC50 = 26 μM and 23 μM; ZIKV IC50 = 28 μM and 19  μM, respectively), two representatives of novel non-nucleoside inhibitors of flavivirus MTases